Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

The actin regulatory protein, cofilin plays a key signaling role in many cells for numerous cellular responses including in proliferation, development, motility, migration, secretion, and growth. In the pancreas it is important in islet insulin secretion, growth of pancreatic cancer cells and in pancreatitis. However, there are no studies on its role or activation in pancreatic acinar cells. To address this question, we studied the ability of Cholecystokinin (CCK) to activate cofilin in pancreatic acinar cells, AR42J cells and CCK1-R transfected Panc-1 cells, the signaling cascades involved and its effect on enzyme secretion and MAPK activation, a key mediator of pancreatic growth. Our results support the conclusion that cofilin activation plays a pivotal convergent role for various cell signaling cascades PKC/PKD, Src, PAK4, JNK, ROCK in CCK-mediated growth/enzyme secretion in pancreatic acini. Recent studies show that in both normal and neoplastic tissues, gastrointestinal hormones (GI) and GI growth factors (GF) may cause cell growth by stimulating multiple intracellular tyrosine/serine/threonine phosphorylation (TyrP) signaling cascades as well as by transactivation of growth factor receptors. However, at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. In the past, we reported that the neuropeptide, neurotensin in lung cancer cells stimulates growth of these tumors while signaling principally by transactivation of a number of EGFR family members including EGFR, HER2, however, it is unclear whether neurotensin also transactivates other EGFR/Neu members such as HER3, hence we examined this question in lung cancer cells. We found that neurotensin in these cells stimulates proliferation by activating HER3 manifested by stimulating the formation of EGFR/HER3 and HER2/HER3 dimers. Recent studies, including ours have demonstrated that in different cells the mechanisms of the ability of these peptides to stimulate tyrosine phosphorylation and receptor tyrosine kinases involves a number of different mechanisms, and this was reviewed in detail for PACAP-VIP, Bombesin, endothelin and neurotensin in an invited review this year. The novel abilities of these GPCRs to activate these tyrosine kinase cascades are demonstrating the importance of these receptors in numerous physiological/pathological processes, particular growth cascades of both normal and cancer tissues, opening new therapeutic approaches. In addition to our experimental studies, we have recently we have written a number of invited reviews and critical analyses which are partially based on our studies of the cellular basis of action of various gastrointestinal peptides that we are studying (bombesin receptor family, VIP-PACAP peptide family, endothelin receptor family, neurotensin). These include papers reporting the effects of activation of a number of these receptors on cancer growth through the transactivation of the EGF receptor family as well as reviews of the possible therapeutic roles of PACAP/VIP and bombesin receptor families in various human diseases and CNS cancers, respectively.